(Adapted from the applicant's abstract): Although a variety of environmental and biologic factors are known to influence the timing of puberty, genetic background is among the most important modulators. The correlation between the timing of pubertal milestones among children and their parents and between monozygotic twins indicates that 48-80% of the variance in pubertal onset is genetically controlled. Regulation of the timing of puberty is, however, unlikely to exhibit classic Mendelian inheritance or be attributable to a single locus; rather, it is likely to be a complex genetic trait that is modulated by variations in multiple genes. Increasing evidence suggests that the presence of particular common variants or combinations of variants within an individual's genome modulate the expression of complex traits, such as the onset of puberty. It is the broad goal of this proposal to identify the genetic factors that regulate the timing of puberty in humans. The proposal is designed to test the hypothesis that the genetic regulation of puberty is polygenic and derives from the effects of common sequence variants. This question will be addressed by: 1) generating a DNA collection from subjects whose pubertal onset occurred extremely early or extremely late and including parental DNA in the collection so that informative association studies can be performed; 2) determining whether the known polymorphisms in the genes for leptin and/or its receptor associate with specific patterns of pubertal onset; 3) extending the analysis to other genes known to modulate hypothalamic-pituitary-gonadal (HPG) function by employing high-throughput screening techniques to identify specific allelic variations that associate with diverse patterns of pubertal onset; and 4) defining the genotype/phenotype correlations across the spectrum from precocious to delayed puberty for those allelic variants that are shown to associate with specific patterns of pubertal onset. Identification of genes that regulate the timing of puberty will greatly enhance the understanding of the HPG axis and will provide insight into abnormal patterns of growth and development, such as central precocious puberty and delayed puberty.